Secondary alcohol substituted triazoles as PDE10 inhibitors

ABSTRACT

The present invention is directed to secondary alcohol substituted triazole compounds which are useful as therapeutic agents for the treatment of central nervous system disorders associated with phosphodiesterase 10 (PDE10). The present invention also relates to the use of such compounds for treating neurological and psychiatric disorders, such as schizophrenia, psychosis or Huntington&#39;s disease, and those associated with striatal hypofunction or basal ganglia dysfunction.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No.PCT/US2013/069380 filed on Nov. 11, 2013, which claims the benefit under35 U.S.C. 119(e) of U.S. Provisional Application No. 61/726,655, filedNov. 15, 2012.

FIELD OF THE INVENTION

The invention relates generally to compounds which act as inhibitors ofthe phosphodiesterase (PDE) 10 enzyme, compositions and therapeutic usesthereof.

BACKGROUND OF THE INVENTION

Schizophrenia is debilitating disorder affecting the psychic and motorfunctions of the brain. It is typically diagnosed in individuals intheir early to mid-twenties and symptoms include hallucinations anddelusions or at the other extreme, anhedonia or social withdrawal.Across the spectrum, the symptoms are indicative of cognitive impairmentand functional disabilities. Notwithstanding improvements inantipsychotic treatments, current therapies, including typical(haloperidol) and atypical (clozapine or olanzapine) antipsychotics,have been less than acceptable and result in an extremely high rate ofnoncompliance or discontinuation of medication. Dissatisfaction withtherapy is attributed to lack of efficacy or intolerable andunacceptable side affects. The side effects have been associated withsignificant metabolic, extrapyramidal, prolactic and cardiac adverseevents. See, Lieberman et al., N. Engl. J. Med. (2005) 353:1209-1223.

While multiple pathways are believed to be involved with thepathogenesis of schizophrenia leading to psychosis and cognitiondeficits, much attention has focused on the role of glutamate/NMDAdysfunction associated with cyclic guanosine monophosphate (cGMP) levelsand the dopaminergic D2 receptor associated with cyclic adenosinemonophosphate (cAMP). These ubiquitous second messengers may beresponsible for altering the function of many intracellular proteins.Cyclic AMP is thought to regulate the activity of cAMP-dependent proteinkinase (PKA), which in turns phosphorylates and regulates many types ofproteins including ion channels, enzymes and transcription factors.Similarly, cGMP may also be responsible for downstream regulation ofkinases and ion channels.

One pathway for affecting the levels of cyclic nucleotides, such as cAMPand cGMP, is to alter or regulate the enzymes that degrade theseenzymes, known as 3′,5′-cyclic nucleotide specific phosphodiesterases(PDEs). The PDE superfamily includes twenty one genes that encode foreleven families of PDEs. These families are further subdivided based oncatalytic domain homology and substrate specificity and include the 1)cAMP specific, PDE4A-D, 7A and 7B, and 8A and 8B, 2) cGMP specific, PDE5A, 6A-C, and 9A, and 3) those that are dual substrate, PDE 1A-C, 2A, 3Aand 3B, 10A, and 11A. The homology between the families, ranging from20% to 45% suggests that it may be possible to develop selectiveinhibitors for each of these subtypes.

The identification of PDE10 was reported by three groups independentlyand was distinguished from other PDEs on the basis of its amino acidsequence, functional properties, and tissue distribution (Fujishige etal., J. Biol. Chem. (1999) 274:18438-18445; Loughney et al., Gene (1999)234: 109-117; Soderling et al., PNAS, USA (1999) 96: 7071-7076). ThePDE10 subtype at present consists of a sole member, PDE10A, havingalternative splice variants at both the N-terminus (three variants) andC-terminus (two variants), but that does not affect the GAF domain inthe N-terminus or the catalytic site in C-terminus. The N-terminussplice variants, PDE10A1 and PDE10A2, differ in that the A2 variant hasa PKA phosphorylation site that upon activation, i.e. PKAphosphorylation in response to elevated cAMP levels, results inintracellular changes to the localization of the enzyme. PDE10A isunique relative to other PDE families also having the conserved GAFdomain in that its ligand is cAMP, while for the other GAF-domain PDEsthe ligand is cGMP (Kehler et al., Expert Opin. Ther. Patents (2007)17(2): 147-158). PDE10A has limited but high expression in the brain andtestes. The high expression in the brain and, in particular, the neuronsof the striatum, unique to PDE10, suggests that inhibitors thereto maybe well suited from treating neurological and psychiatric disorders andconditions. For additional background information on PDE10 compounds seeU.S. Ser. Nos. 61/544,055 and 61/544,065, both filed Oct. 6, 2011;WO2012/044561 and PCT application number PCT/US12/051522, filed Aug. 20,2012.

Inhibition of PDE10 is believed to be useful in the treatment ofschizophrenia and a wide variety of conditions or disorders that wouldbenefit from increasing levels of cAMP and/or cGMP within neurons,including a variety neurological, psychotic, anxiety and/or movementdisorders. Accordingly, agents that inhibit PDE10 and especially PDE10Amay be desirable as therapeutics for neurological and psychiatricdisorders.

SUMMARY OF THE INVENTION

The present invention is directed to secondary alcohol substitutedtriazole compounds which may be useful as therapeutic agents for thetreatment of central nervous system disorders associated withphosphodiesterase 10 (PDE10). The present invention also relates to theuse of such compounds for treating neurological and psychiatricdisorders, such as schizophrenia, psychosis or Huntington's disease, andthose associated with striatal hypofunction or basal gangliadysfunction.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:

A represents

R represents H or C₁₋₆alkyl;

-   R¹ is selected from the groups consisting of (CH₂)_(n)C₁₋₄haloalkyl,    C₁₋₆alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ wary, said alkyl cycloalkyl, and    aryl is unsubstituted or substituted with 1 to 3 groups of R^(a);-   R² is selected from the group consisting of H, O—R, CN,    O(CH₂)_(n)OR, OCHR(CH₂)_(n)OR, SR, SO₂R, S(O)R, N(R)₂, C(O)N(R)₂,    C₁₋₃ haloalkyl, O(CH₂)_(n)C₁₋₃haloalkyl, O(CH₂)_(n)C₃₋₆cycloalkyl,    (CH₂)_(n)C₅₋₁₀heterocycle, C₁₋₆alkyl, and C₃₋₁₀cycloalkyl, said    alkyl, cycloalkyl, and heterocycle is unsubstituted or substituted    with 1 to 3 groups of R^(a);-   R^(a) is selected from the group consisting of:-   (1) halogen,-   (2) hydroxyl,-   (3) C₁₋₆alkyl,-   (4) —(CH₂)_(n)O—R,-   (5) (CH₂)_(n) C₆₋₁₀aryl,-   (6) (CH₂)_(n)C₅₋₁₀ heterocycle,-   (7) OC₁₋₅ haloalkyl;-   (8) CO₂R;-   (9) C(O)N(R)₂;-   (10) (CH₂)_(n)C(O)R;-   (11) CN,-   (12) (CH₂)_(n)N(R)₂;-   (13) (CH₂)_(n)C₃₋₆cycloalkyl,-   (14) (CH₂)_(n)C₁₋₃ haloalkyl;-   n represents 0-4,-   or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds wherein A is

An embodiment of the present invention includes compounds wherein A is

An embodiment of the present invention includes compounds wherein R¹ is(CH₂)_(n)C₁₋₄haloalkyl or C₁₋₆alkyl.

An embodiment of the present invention includes compounds wherein R¹ isC₁₋₆ alkyl. A subembodiment of this invention is realized when R¹ ismethyl, ethyl or propyl. Another subembodiment of this invention isrealized when R¹ is methyl.

An embodiment of the present invention includes compounds wherein R¹ is(CH₂)_(n)C₁₋₄ haloalkyl. A subembodiment of this invention is realizedwhen R¹ is CF₃.

An embodiment of the present invention includes compounds wherein R¹ isoptionally substituted C₆₋₁₀ aryl. A subembodiment of this invention isrealized when R¹ is optionally substituted phenyl.

An embodiment of the present invention includes compounds wherein R¹ isC₃₋₆ cycloalkyl. A subembodiment of this invention is realized when R¹is cyclopropyl, cyclobutyl, or cyclohexyl. A further subembodiment ofthis invention is realized when R¹ is cyclohexyl.

Another embodiment of the present invention includes compounds whereinR² is selected from the group consisting of O—R, CN, C₁₋₃ haloalkyl,C₁₋₆alkyl, and C₃₋₁₀cycloalkyl, said alkyl and cycloalkyl isunsubstituted or substituted with 1 to 3 groups of R^(a). Asubembodiment of this invention is realized when R² is methyl, ethyl,propyl, CF₃, cyclopropyl. Another subembodiment of this invention isrealized when R² is methyl. Another subembodiment of this invention isrealized when R² is CF₃. Another subembodiment of this invention isrealized when R² is cyclopropyl.

Another embodiment of the present invention includes compounds whereinR¹ is (CH₂)_(n)C₁₋₃haloalkyl, C₁₋₆alkyl, or C₃₋₆cycloalkyl, and R² isselected from the group consisting of O—R, CN, C₁₋₃ haloalkyl,C₁₋₆alkyl, and C₃₋₁₀cycloalkyl, said alkyl unsubstituted or substitutedwith 1 to 3 groups of R^(a).

Another embodiment of the present invention includes compounds wherein Ris methyl, R¹ is methyl, ethyl, propyl, CF₃, or cyclohexyl and R² ismethyl, ethyl, propyl, CF₃, or cyclopropyl

An embodiment of the present invention includes compounds represented bystructural formula Ia:

wherein R¹, and R² are as originally described. A subembodiment of theinvention of formula Ia is realized when R¹ is methyl, ethyl, propyl,CF₃, phenyl, or cyclohexyl. A subembodiment of formula Ia is realizedwhen R¹ is methyl, ethyl, or propyl. Another subembodiment of theinvention of formula Ia is realized when R² is methyl, ethyl, propyl,CF₃, or cyclopropyl. A subembodiment of formula Ia is realized when R¹is methyl, ethyl, or propyl and R² is methyl, CF₃, or cyclopropyl. Asubembodiment of formula Ia is realized when R¹ is methyl, and R² ismethyl, or CF₃.

An embodiment of the present invention includes compounds represented bystructural formula Iaa:

wherein R¹, and R² are as originally described. A subembodiment of theinvention of formula Iaa is realized when R¹ is methyl, ethyl, propyl,CF₃, phenyl, or cyclohexyl. A subembodiment of formula Iaa is realizedwhen R¹ is methyl, ethyl, or propyl. Another subembodiment of theinvention of formula Iaa is realized when R² is methyl, ethyl, propyl,CF₃, or cyclopropyl. A subembodiment of formula Iaa is realized when R¹is methyl, ethyl, or propyl and R² is methyl, CF₃, or cyclopropyl. Asubembodiment of formula Iaa is realized when R¹ is methyl, and R² ismethyl, or CF₃.

An embodiment of the present invention of formula I includes compoundsrepresented by structural formula Ib:

wherein R¹, and R² are as originally described. A subembodiment of theinvention of formula Ib is realized when R¹ is methyl, ethyl, propyl,CF₃, phenyl, or cyclohexyl. A subembodiment of formula Ib is realizedwhen R¹ is methyl, ethyl, or propyl. Another subembodiment of theinvention of formula Ib is realized when R² is methyl, ethyl, propyl,CF₃, or cyclopropyl. A subembodiment of formula Ib is realized when R¹is methyl, ethyl, or propyl and R² is methyl, CF₃, or cyclopropyl. Asubembodiment of formula Ib is realized when R¹ is methyl, and R² ismethyl, or CF₃.

Examples of compounds of this invention include:

-   1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;-   (S)-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;-   (R)-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;-   1-(3-methyl-1-(6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;-   1-(1-(2-methoxy-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-3-methyl-1H-1,2,4-triazol-5-yl)ethanol;-   1-(1-(2-cyclopropyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-3-methyl-1H-1,2,4-triazol-5-yl)ethanol;-   2,2,2-trifluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;-   (S)-2,2,2-trifluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;-   (R)-2,2,2-trifluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;-   2,2-difluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;-   2-fluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;-   (S)-cyclohexyl(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)methanol;-   (R)-cyclohexyl(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)methanol;-   (S)-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)(phenyl)methanol;-   (R)-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)(phenyl)methanol;-   1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol;-   2-methyl-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol;-   cyclopropyl(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)methanol;-   3,3,3-trifluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol;-   1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;-   (R)-1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;-   (S)-1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;-   (R)-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)(phenyl)methanol;-   (S)-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)(phenyl)methanol;-   2,2,2-trifluoro-1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;-   1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol;-   2-methyl-1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol;-   1-(3-methyl-1-(6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)-2-(trifluoromethyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;-   (S)-1-(3-methyl-1-(6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)-2-(trifluoromethyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;-   1-(1-(2-cyclopropyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-3-methyl-1H-1,2,4-triazol-5-yl)ethanol-   (S)-1-(1-(2-cyclopropyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-3-methyl-1H-1,2,4-triazol-5-yl)ethanol;    or pharmaceutically acceptable salts thereof.

Specific embodiments of the present invention include a compound whichis selected from the group consisting of the subject compounds of theExamples herein and pharmaceutically acceptable salts thereof andindividual enantiomers and diastereomers thereof.

When any variable (e.g. aryl, heterocycle, R¹, R⁵ etc.) occurs more thanone time in any constituent, its definition on each occurrence isindependent at every other occurrence. Also, combinations ofsubstituents/or variables are permissible only if such combinationsresult in stable compounds.

As used herein, “alkyl” encompasses groups having the prefix “alk” suchas, for example, alkoxy, alkanoyl, alkenyl, and alkynyl and means carbonchains which may be linear or branched or combinations thereof. Examplesof alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-and tert-butyl, pentyl, hexyl, and heptyl. “Alkenyl” refers to ahydrocarbon radical straight, branched or cyclic containing from 2 to 10carbon atoms and at least one carbon to carbon double bond. Preferredalkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.Preferably, alkenyl is C₂-C₆ alkenyl. Preferred alkynyls are C₂-C₆alkynyl.

“Alkenyl,” “alkynyl” and other like terms include carbon chainscontaining at least one unsaturated C—C bond.

As used herein, “haloalkyl” refers to an alkyl substituent as describedherein containing at least one halogen substituent.

The term “cycloalkyl” refers to a saturated hydrocarbon containing onering having a specified number of carbon atoms. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “C₁₋₆” includes alkyls containing 6, 5, 4, 3, 2, or 1 carbonatoms

The term “alkoxy” or “O-alkyl” as used herein, alone or in combination,includes an alkyl group connected to the oxy connecting atom. The term“alkoxy” also includes alkyl ether groups, where the term ‘alkyl’ isdefined above, and ‘ether’ means two alkyl groups with an oxygen atombetween them. Examples of suitable alkoxy groups include methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy,methoxymethane (also referred to as ‘dimethyl ether’), and methoxyethane(also referred to as ‘ethyl methyl ether’).

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 members in each ring, wherein at leastone ring is aromatic. Examples of such aryl elements include phenyl,napthyl, tetrahydronapthyl, indanyl, or biphenyl.

The term heterocycle, heterocyclyl, or heterocyclic, as used herein,represents a stable 5- to 7-membered monocyclic or stable 8- to11-membered bicyclic heterocyclic ring which is either saturated orunsaturated, and which consists of carbon atoms and from one to fourheteroatoms selected from the group consisting of N, O, and S, andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The heterocyclic ring maybe attached at any heteroatom or carbon atom which results in thecreation of a stable structure. The term heterocycle or heterocyclicincludes heteroaryl moieties. Examples of such heterocyclic elementsinclude, but are not limited to, azepinyl, benzimidazolyl,benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl,benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl, imidazolyl,indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl,isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl,naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl,2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl,pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl,pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl,thienofuryl, thienothienyl, thienyl and triazolyl.

The term “heteroaryl”, as used herein except where noted, represents astable 5- to 7-membered monocyclic- or stable 9- to 10-membered fusedbicyclic heterocyclic ring system which contains an aromatic ring, anyring of which may be saturated, such as piperidinyl, partiallysaturated, or unsaturated, such as pyridinyl, and which consists ofcarbon atoms and from one to four heteroatoms selected from the groupconsisting of N, O and S, and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized, and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached at any heteroatom or carbon atom whichresults in the creation of a stable structure. Examples of suchheteroaryl groups include, but are not limited to, benzimidazole,benzisothiazole, benzisoxazole, benzofuran, benzothiazole,benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan,furazan, imidazole, indazole, indole, indolizine, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine,pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole,thiadiazole, thiazole, thiophene, triazine, triazole, and N-oxidesthereof.

The term “heteroatom” means O, S or N, selected on an independent basis.

A moiety that is substituted is one in which one or more hydrogens havebeen independently replaced with another chemical substituent. As anon-limiting example, substituted phenyls include 2-flurophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2,4 fluor-3-propylphenyl. Asanother non-limiting example, substituted n-octyls include 2, 4dimethyl-5-ethyl-octyl and 3-cyclopentyloctyl. Included within thisdefinition are methylenes (—CH₂—) substituted with oxygen to formcarbonyl (—CO—).

Unless otherwise stated, as employed herein, when a moiety (e.g.,cycloalkyl, hydrocarbyl, aryl, alkyl, heteroaryl, heterocyclic, urea,etc.) is described as “optionally substituted” it is meant that thegroup optionally has from one to four, preferably from one to three,more preferably one or two, non-hydrogen substituents. Suitablesubstituents include, without limitation, halo, hydroxy, oxo (e.g., anannular —CH— substituted with oxo is —C(O)—), nitro, halohydrocarbyl,hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino,alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl,alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido,aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.Preferred substituents, which are themselves not further substituted(unless expressly stated otherwise) are:

-   -   (a) halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino,        guanidino, and    -   (b) C₁-C₆ alkyl or alkenyl or arylalkyl imino, carbamoyl, azido,        carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl,        arylalkyl, C₁-C₈ alkyl, SO₂CF₃, CF₃, SO₂Me, C₁-C₈ alkenyl, C₁-C₈        alkoxy, C₁-C₈ alkoxycarbonyl, aryloxycarbonyl, C₂-C₈ acyl, C₂-C₈        acylamino, C₁-C₈ alkylthio, arylalkylthio, arylthio,        C₁-C₈alkylsulfinyl, arylalkylsulfnyl, arylsulfnyl, C₁-C₈        alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, C₀-C₆        N-alkylcarbamoyl, C₂-C₁₅ N,N dialkylcarbamoyl, C₃-C₇ cycloalkyl,        aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a        cycloalkyl or heterocycle or another aryl ring, C₃-C₇        heterocycle, or any of these rings fused or spiro-fused to a        cycloalkyl, heterocyclyl, or aryl, wherein each of the foregoing        is further optionally substituted with one more moieties listed        in (a), above.

“Halogen” or “halo” refer to fluorine, chlorine, bromine and iodine.

The term “mammal” “mammalian” or “mammals” includes humans, as well asanimals, such as dogs, cats, horses, pigs and cattle.

All patents, patent applications and publications cited herein, whethersupra or infra, are hereby incorporated by reference in their entiretyand are deemed representative of the prevailing state of the art.

As used in this specification and the appended claims, the singularforms “a,” “an” and “the” include plural references unless the contentclearly dictates otherwise. Thus, for example, reference to “a primer”includes two or more such primers, reference to “an amino acid” includesmore than one such amino acid, and the like.

Compounds described herein may contain one or more double bonds and maythus give rise to cis/trans isomers as well as other conformationalisomers. The present invention includes all such possible isomers aswell as mixtures of such isomers unless specifically stated otherwise.

The independent syntheses of the enantiomerically or diastereomericallyenriched compounds, or their chromatographic separations, may beachieved as known in the art by appropriate modification of themethodology disclosed herein. Their absolute stereochemistry may bedetermined by the x-ray crystallography of crystalline products orcrystalline intermediates that are derivatized, if necessary, with areagent containing an asymmetric center of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers or diastereomers are isolated. The separationcan be carried out by methods well known in the art, such as thecoupling of a racemic mixture of compounds to an enantiomerically purecompound to form a diastereomeric mixture, followed by separation of theindividual diastereomers by standard methods, such as fractionalcrystallization or chromatography. The coupling reaction is often theformation of salts using an enantiomerically pure acid or base. Thediastereomeric derivatives may then be converted to the pure enantiomersby cleavage of the added chiral residue. The racemic mixture of thecompounds can also be separated directly by chromatographic methodsusing chiral stationary phases, which methods are well known in the art.

Alternatively, any enantiomer or diastereomer of a compound may beobtained by stereoselective synthesis using optically pure startingmaterials or reagents of known configuration by methods well known inthe art.

In the compounds of generic Formula I, Ia, Iaa, and Ib the atoms mayexhibit their natural isotopic abundances, or one or more of the atomsmay be artificially enriched in a particular isotope having the sameatomic number, but an atomic mass or mass number different from theatomic mass or mass number predominantly found in nature. The presentinvention is meant to include all suitable isotopic variations of thecompounds of generic Formula I. For example, different isotopic forms ofhydrogen (H) include protium (¹H) and deuterium (²H). Protium is thepredominant hydrogen isotope found in nature. Enriching for deuteriummay afford certain therapeutic advantages, such as increasing in vivohalf-life or reducing dosage requirements, or may provide a compounduseful as a standard for characterization of biological samples.Isotopically-enriched compounds within generic Formula I can be preparedwithout undue experimentation by conventional techniques well known tothose skilled in the art or by processes analogous to those described inthe Schemes and Examples herein using appropriate isotopically-enrichedreagents and/or intermediates.

It will be understood that, as used herein, references to the compoundsof present invention are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds or inother synthetic manipulations. The compounds of the present inventionmay be administered in the form of a pharmaceutically acceptable salt.The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, cupric,cuprous, ferric, ferrous, lithium, magnesium, manganic, manganous,potassium, sodium, zinc and the like salts. Particular embodimentsinclude the ammonium, calcium, magnesium, potassium, and sodium salts.Salts in the solid form may exist in more than one crystal structure,and may also be in the form of hydrates. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol,2-dimethylamino-ethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like. When the compound of the present inventionis basic, salts may be prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid, and the like. Particular embodiments citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids. It will be understood that, as used herein, referencesto the compounds of the present invention are meant to also include thepharmaceutically acceptable salts.

Exemplifying the invention are the specific compounds disclosed in theExamples and herein. The subject compounds may be useful in a method oftreating a neurological or psychiatric disorder associated with PDE10dysfunction in a patient such as a mammal in need of such inhibitioncomprising the administration of an effective amount of the compound. Inaddition to primates, especially humans, a variety of other mammals maybe treated according to the method of the present invention. The subjectcompounds may be useful in a method of inhibiting PDE10 activity in apatient such as a mammal in need of such inhibition comprising theadministration of an effective amount of the compound. The subjectcompounds also may be useful for treating a neurological or psychiatricdisorder associated with striatal hypofunction or basal gangliadysfunction in a mammalian patient in need thereof. In addition toprimates, especially humans, a variety of other mammals may be treatedaccording to the method of the present invention.

The present invention is directed to a compound of the present inventionor a pharmaceutically acceptable salt thereof for use in medicine. Thepresent invention is further directed to a use of a compound of thepresent invention or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for treating a neurological or psychiatricdisorder associated with PDE10 dysfunction in a mammalian patient inneed thereof. The present invention is further directed to a use of acompound of the present invention or a pharmaceutically acceptable saltthereof for the manufacture of a medicament for treating a neurologicalor psychiatric disorder associated with striatal hypofunction or basalganglia dysfunction in a mammalian patient in need thereof.

“Treating” or “treatment of” a disease state includes: 1) preventing thedisease state, i.e. causing the clinical symptoms of the disease statenot to develop in a subject that may be exposed to or predisposed to thedisease state, but does not yet experience or display symptoms of thedisease state; 2) inhibiting the disease state, i.e., arresting thedevelopment of the disease state or its clinical symptoms; 3) orrelieving the disease state, i.e., causing temporary or permanentregression of the disease state or its clinical symptoms.

The subject treated in the present methods is generally a mammal, inparticular, a human being, male or female, in whom therapy is desired.The term “therapeutically effective amount” means the amount of thesubject compound that will elicit the biological or medical response ofa tissue, system, animal or human that is being sought by theresearcher, veterinarian, medical doctor or other clinician. It isrecognized that one skilled in the art may affect the neurological andpsychiatric disorders by treating a patient presently afflicted with thedisorders or by prophylactically treating a patient afflicted with suchdisorders with an effective amount of the compound of the presentinvention. As used herein, the terms “treatment” and “treating” refer toall processes wherein there may be a slowing, interrupting, arresting,controlling, or stopping of the progression of the neurological andpsychiatric disorders described herein, but does not necessarilyindicate a total elimination of all disorder symptoms, as well as theprophylactic therapy to retard the progression or reduce the risk of thenoted conditions, particularly in a patient who is predisposed to suchdisease or disorder.

Applicants propose that inhibitors of PDE10 and, in particularinhibitors of PDE10A, may provide therapeutic benefit to thoseindividuals suffering from psychiatric and cognitive disorders. Theunique and exclusive distribution of PDE10A in the medium spinyprojection neurons of the striatum, which form the principle site forcortical and dopaminergic input within basal ganglia, suggests that itmay be possible and desirable to identify inhibitors of PDE10 toameliorate or eliminate unwanted cellular signaling within this site.Without wishing to be bound by any theory, Applicants believe thatinhibition of PDE10A in the striatum may result in increased cAMP/cGMPsignaling and striatal output, which has the potential to restorebehavioral inhibition that is impaired in cognitive disease such asschizophrenia. Regulation and integration of glutamatergic anddopaminergic inputs may enhance cognitive behavior, while suppressing orreducing unwanted behavior. Thus, in one embodiment compounds of theinvention provide a possible method for treating or amelioratingdiseases or conditions in which striatal hypofunction is a prominentfeature or ones in which basal ganglia dysfunction plays a role, suchas, Parkinson's disease, Huntington's disease, schizophrenia,obsessive-compulsive disorders, addiction and psychosis. Otherconditions for which the inhibitors described herein may have adesirable and useful effect include those requiring a reduction inactivity and reduced response to psychomotor stimulants or where itwould be desirable to reduce conditional avoidance responses, which isoften predictive of clinical antipsychotic activity.

As used herein, the term “'selective PDE10 inhibitor” refers to anorganic molecule that effectively inhibits an enzyme from the PDE10family to a greater extent than enzymes from the PDE 1-9 or PDE11families. In one embodiment, a selective PDE10 inhibitor is an organicmolecule having a Ki for inhibition of PDE10 that is less than or aboutone-tenth that for a substance that is an inhibitor for another PDEenzyme. In other words, the organic molecule inhibits PDE10 activity tothe same degree at a concentration of about one-tenth or less than theconcentration required for any other PDE enzyme. Preferably, a selectivePDE10 inhibitor is an organic molecule, having a Ki for inhibition ofPDE10 that is less than or about one-hundredth that for a substance thatis an inhibitor for another PDE enzyme. In other words, the organicmolecule inhibits PDE10 activity to the same degree at a concentrationof about one-hundredth or less than the concentration required for anyother PDE enzyme. A “selective PDE10 inhibitor” can be identified, forexample, by comparing the ability of an organic molecule to inhibitPDE10 activity to its ability to inhibit PDE enzymes from the other PDEfamilies. For example, an organic molecule may be assayed for itsability to inhibit PDE10 activity, as well as PDE1A, PDE1B, PDE1C,PDE2A, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE5A, PDE6A, PDE6B,PDE6C, PDE7A, PDE7B, PDE8A, PDE8B, PDE9A, and/or PDE11A.

Phosphodiesterase enzymes including PDE10 have been implicated in a widerange of biological functions. This has suggested a potential role forthese enzymes in a variety of disease processes in humans or otherspecies. The compounds of the present invention may have utility intreating a variety of neurological and psychiatric disorders.

In a specific embodiment, compounds of the present invention may providea method for treating schizophrenia or psychosis comprisingadministering to a patient in need thereof an effective amount of acompound of the present invention. The Diagnostic and Statistical Manualof Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association,Washington D.C.) provides a diagnostic tool that includes paranoid,disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorders. As used herein, the term“schizophrenia or psychosis” includes the diagnosis and classificationof these mental disorders as described in DSM-IV-TR and the term isintended to include similar disorders described in other sources.Disorders and conditions encompassed herein include, but are not limitedto, conditions or diseases such as schizophrenia or psychosis, includingschizophrenia (paranoid, disorganized, catatonic, undifferentiated, orresidual type), schizophreniform disorder, schizoaffective disorder, forexample of the delusional type or the depressive type, delusionaldisorder, psychotic disorder, brief psychotic disorder, shared psychoticdisorder, psychotic disorder due to a general medical condition andsubstance-induced or drug-induced (for example psychosis induced byalcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants,opioids, phencyclidine, ketamine and other dissociative anaesthetics,and other psychostimulants), psychosispsychotic disorder, psychosisassociated with affective disorders, brief reactive psychosis,schizoaffective psychosis, “schizophrenia-spectrum” disorders such asschizoid or schizotypal personality disorders, personality disorder ofthe paranoid type, personality disorder of the schizoid type, illnessassociated with psychosis (such as major depression, manic depressive(bipolar) disorder, Alzheimer's disease and post-traumatic stresssyndrome), including both the positive and the negative symptoms ofschizophrenia and other psychoses.

In another specific embodiment, the compounds of the present inventionmay provide a method for treating cognitive disorders comprisingadministering to a patient in need thereof an effective amount of acompound of the present invention. The DSM-IV-TR also provides adiagnostic tool that includes cognitive disorders including dementia,delirium, amnestic disorders and age-related cognitive decline. As usedherein, the term “cognitive disorders” includes the diagnosis andclassification of these disorders as described in DSM-IV-TR and the termis intended to include similar disorders described in other sources.Disorders and conditions encompassed herein include, but are not limitedto, disorders that comprise as a symptom a deficiency in attentionand/or cognition, such as dementia (associated with Alzheimer's disease,ischemia, multi-infarct dementia, trauma, intracranial tumors, cerebraltrauma, vascular problems or stroke, alcoholic dementia or otherdrug-related dementia, AIDS, HIV disease, Parkinson's disease,Huntington's disease, Pick's disease, Creutzfeldt Jacob disease,perinatal hypoxia, other general medical conditions or substance abuse),Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, andFronto temperal dementia, delirium, amnestic disorders or age relatedcognitive decline.

In another specific embodiment, compounds of the present invention mayprovide a method for treating anxiety disorders comprising administeringto a patient in need thereof an effective amount of a compound of thepresent invention. The DSM-IV-TR also provides a diagnostic tool thatincludes anxiety disorders as generalized anxiety disorder,obsessive-compulsive disorder and panic attack. As used herein, the term“anxiety disorders” includes the diagnosis and classification of thesemental disorders as described in DSM-IV-TR and the term is intended toinclude similar disorders described in other sources. Disorders andconditions encompassed herein include, but are not limited to, anxietydisorders such as, acute stress disorder, agoraphobia, generalizedanxiety disorder, obsessive-compulsive disorder, panic attack, panicdisorder, post-traumatic stress disorder, separation anxiety disorder,social phobia, specific phobia, substance-induced anxiety disorder andanxiety due to a general medical condition.

In another specific embodiment, compounds of the present invention mayprovide a method for treating substance-related disorders and addictivebehaviors comprising administering to a patient in need thereof aneffective amount of a compound of the present invention. The DSM-IV-TRalso provides a diagnostic tool that includes persisting dementia,persisting amnestic disorder, psychotic disorder or anxiety disorderinduced by substance abuse, and tolerance of, dependence on orwithdrawal from substances of abuse. As used herein, the term“substance-related disorders and addictive behaviors” includes thediagnosis and classification of these mental disorders as described inDSM-IV-TR and the term is intended to include similar disordersdescribed in other sources. Disorders and conditions encompassed hereininclude, but are not limited to, substance-related disorders andaddictive behaviors, such as substance-induced delirium, persistingdementia, persisting amnestic disorder, psychotic disorder or anxietydisorder, drug addiction, tolerance, and dependence or withdrawal fromsubstances including alcohol, amphetamines, cannabis, cocaine,hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives,hypnotics or anxiolytics.

In another specific embodiment, compounds of the present invention mayprovide a method for treating obesity or eating disorders associatedwith excessive food intake, and complications associated therewith,comprising administering to a patient in need thereof an effectiveamount of a compound of the present invention. At present, obesity isincluded in the tenth edition of the International Classification ofDiseases and Related Health Problems (ICD-10) (1992 World HealthOrganization) as a general medical condition. The DSM-IV-TR alsoprovides a diagnostic tool that includes obesity in the presence ofpsychological factors affecting medical condition. As used herein, theterm “obesity or eating disorders associated with excessive food intake”includes the diagnosis and classification of these medical conditionsand disorders described in ICD-10 and DSM-IV-TR and the term is intendedto include similar disorders described in other sources. Disorders andconditions encompassed herein include, but are not limited to, obesity,bulimia nervosa and compulsive eating disorders.

In another specific embodiment, compounds of the present invention mayprovide a method for treating mood and depressive disorders comprisingadministering to a patient in need thereof an effective amount of acompound of the present invention. As used herein, the term “mood anddepressive disorders” includes the diagnosis and classification of thesemedical conditions and disorders described in the DSM-IV-TR and the termis intended to include similar disorders described in other sources.Disorders and conditions encompassed herein include, but are not limitedto, bipolar disorders, mood disorders including depressive disorders,major depressive episode of the mild, moderate or severe type, a manicor mixed mood episode, a hypomanic mood episode, a depressive episodewith atypical features, a depressive episode with melancholic features,a depressive episode with catatonic features, a mood episode withpostpartum onset, post-stroke depression; major depressive disorder,dysthymic disorder, minor depressive disorder, premenstrual dysphoricdisorder, post-psychotic depressive disorder of schizophrenia, a majordepressive disorder superimposed on a psychotic disorder such asdelusional disorder or schizophrenia, a bipolar disorder, for example,bipolar I disorder, bipolar II disorder, cyclothymic disorder,depression including unipolar depression, seasonal depression andpost-partum depression, premenstrual syndrome (PMS) and premenstrualdysphoric disorder (PDD), mood disorders due to a general medicalcondition, and substance-induced mood disorders.

In another specific embodiment, compounds of the present invention mayprovide a method for treating pain comprising administering to a patientin need thereof an effective amount of a compound of the presentinvention. Particular pain embodiments are bone and joint pain(osteoarthritis), repetitive motion pain, dental pain, cancer pain,myofascial pain (muscular injury, fibromyalgia), perioperative pain(general surgery, gynecological), chronic pain and neuropathic pain.

In other specific embodiments, compounds of the invention may providemethods for treating other types of cognitive, learning and mentalrelated disorders including, but not limited to, learning disorders,such as a reading disorder, a mathematics disorder, or a disorder ofwritten expression, attention-deficit/hyperactivity disorder,age-related cognitive decline, pervasive developmental disorderincluding autistic disorder, attention disorders such asattention-deficit hyperactivity disorder (ADHD) and conduct disorder; anNMDA receptor-related disorder, such as autism, depression, benignforgetfulness, childhood learning disorders and closed head injury; aneurodegenerative disorder or condition, such as neurodegenerationassociated with cerebral trauma, stroke, cerebral infarct, epilepticseizure, neurotoxin poisoning, or hypoglycemia-inducedneurodegeneration; multi-system atrophy; movement disorders, such asakinesias and akinetic-rigid syndromes (including, Parkinson's disease,drug-induced parkinsonism, post-encephalitic parkinsonism, progressivesupranuclear palsy, multiple system atrophy, corticobasal degeneration,parkinsonism-ALS dementia complex and basal ganglia calcification),medication-induced parkinsonism (such as, neuroleptic-inducedparkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acutedystonia, neuroleptic-induced acute akathisia, neuroleptic-inducedtardive dyskinesia and medication-induced postural tremor), Huntington'sdisease, dyskinesia associated with dopamine agonist therapy, Gilles dela Tourette's syndrome, epilepsy, muscular spasms and disordersassociated with muscular spasticity or weakness including tremors;dyskinesias, including tremor (such as, rest tremor, postural tremor,intention tremor and essential tremor), restless leg syndrome, chorea(such as Sydenham's chorea, Huntington's disease, benign hereditarychorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea andhemiballism), myoclonus (including, generalised myoclonus and focalmyoclonus), tics (including, simple tics, complex tics and symptomatictics), dystonia (including, generalised, iodiopathic, drug-induced,symptomatic, paroxymal, and focal (such as blepharospasm, oromandibular,spasmodic, spasmodic torticollis, axial dystonia, hemiplegic anddystonic writer's cramp)); urinary incontinence; neuronal damage(including ocular damage, retinopathy or macular degeneration of theeye, tinnitus, hearing impairment and loss, and brain edema); emesis;and sleep disorders, including insomnia and narcolepsy.

Of the disorders above, the treatment of schizophrenia, bipolardisorder, depression, including unipolar depression, seasonal depressionand post-partum depression, premenstrual syndrome (PMS) and premenstrualdysphoric disorder (PDD), learning disorders, pervasive developmentaldisorders, including autistic disorder, attention disorders includingAttention-Deficit/Hyperactivity Disorder, autism, tic disordersincluding Tourette's disorder, anxiety disorders including phobia andpost traumatic stress disorder, cognitive disorders associated withdementia, AIDS dementia, Alzheimer's, Parkinson's, Huntington's disease,spasticity, myoclonus, muscle spasm, tinnitus and hearing impairment andloss are of particular importance.

The activity of the compounds in accordance with the present inventionas PDE10 inhibitors may be readily determined without undueexperimentation using a fluorescence polarization (FP) methodology thatis well known in the art (Huang, W., et al., J. Biomol Screen, 2002, 7:215). In particular, the compounds of the following examples hadactivity in reference assays by exhibiting the ability to inhibit thehydrolysis of the phosphosphate ester bond of a cyclic nucleotide. Anycompound exhibiting a Ki (inhibitory constant) below 1 μM would beconsidered a PDE10 inhibitor as defined herein.

In a typical experiment the PDE10 inhibitory activity of the compoundsof the present invention was determined in accordance with the followingexperimental method. PDE10A2 was amplified from human fetal brain cDNA(Clontech, Mountain View, Calif.) using a forward primer correspondingto nucleotides 56-77 of human PDE10A2 (Accession No. AF127480, GenbankIdentifier 4894716), containing a Kozak consensus sequence, and areverse primer corresponding to nucleotides 2406-2413 of human PDE10A2(Accession No. AF127480, Genbank Identifier 4894716). Amplification withEasy-A polymerase (Stratagene, La Jolla, Calif.) was 95° C. for 2minutes followed by thirty three cycles of 95° C. for 40 seconds, 55° C.for 30 seconds, and 72° C. for 2 minutes 48 seconds. Final extension was72° C. for 7 minutes. The PCR product was TA cloned into pcDNA3.2-TOPO(Invitrogen, Carlsbad, Calif.) according to standard protocol. AD293cells with 70-80% confluency were transiently transfected with humanPDE10A2/pcDNA3.2-TOPO using Lipofectamine 2000 according to manufacturerspecifications (Invitrogen, Carlsbad, Calif.). Cells were harvested 48hours post-transfection and lysed by sonication (setting 3, 10×5 secpulses) in a buffer containing 20 mM HEPES, 1 mM EDTA and proteaseinhibitor cocktail (Roche). Lysate was collected by centrifugation at75,000×g for 20 minutes. Supernatant containing the cytoplasmic fractionwas used for evaluation of PDE10A2 activity. The fluorescencepolarization assay for cyclic nucleotide phosphodiesterases wasperformed using an IMAP® FP kit supplied by Molecular Devices,Sunnyvale, Calif. (product # R8139). IMAP® technology has been appliedpreviously to phosphodiesterase assays (Huang, W., et al., J. BiomolScreen, 2002, 7: 215). Assays were performed at room temperature in384-well microtiter plates with an incubation volume of 20.2 μL.Solutions of test compounds were prepared in DMSO and serially dilutedwith DMSO to yield 8 μL of each of 10 solutions differing by 3-fold inconcentration, at 32 serial dilutions per plate. 100% inhibition isdetermined using a known PDE10 inhibitor, which can be any compound thatis present at 5,000 times its Ki value in the assay described asfollows, such as papaverine (see Siuciak, et al. Neuropharmacology(2006) 51:386-396; Becker, et al. Behav Brain Res (2008) 186(2):155-60;Threlfell, et al., J Pharmacol Exp Ther (2009) 328(3):785-795),2-{4-[pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]phenoxymethyl}quinolinesuccinic acid or2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]quinolinesuccinic acid (see Schmidt, et al. J Pharmacol Exp Ther (2008)325:681-690; Threlfell, et al., J Pharmacol Exp Ther (2009) 328(3):785-795). 0% of inhibition is determined by using DMSO (1% finalconcentrations).

A Labcyte Echo 555 (Labcyte, Sunnyvale, Calif.) is used to dispense 200nL from each well of the titration plate to the 384 well assay plate. Asolution of enzyme (1/1600 dilution from aliquots; sufficient to produce20% substrate conversion) and a separate solution of FAM-labeled cAMPPDE from Molecular Devices (product # R7506), at a final concentrationof 50 nM are made in the assay buffer (10 mM Tris HCl, pH 7.2, 10 mMMgCl₂, 0.05% NaN₃ 0.01% Tween-20, and 1 mM DTT). The enzyme and thesubstrate are then added to the assay plates in two consecutiveadditions of 10 μL, and then shaken to mix. The reaction is allowed toproceed at room temperature for 30 minutes. A binding solution is thenmade from the kit components, comprised of 80% Solution A, 20% SolutionB and binding reagent at a volume of 1/600 the total binding solution.The enzymatic reaction is stopped by addition of 60 μL of the bindingsolution to each well of the assay plates and the plates are sealed andshaken for 10 seconds. The plate was incubated at room temperature forat least one hour prior to determining the fluorescence polarization(FP). The parallel and perpendicular fluorescence of each well of theplate was measured using a Perkin Elmer EnVision™ plate reader (Waltham,Mass.).

Fluorescence polarization (mP) was calculated from the parallel (S) andperpendicular (P) fluorescence of each sample well and the analogousvalues for the median control well, containing only substrate (So andPo), using the following equation:Polarization (mP)=1000*(S/So−P/Po)/(S/So+P/Po).

Dose-inhibition profiles for each compound were characterized by fittingthe mP data to a four-parameter equation given below. The apparentinhibition constant (K_(I)), the maximum inhibition at the low plateaurelative to “100% Inhibition Control” (Imax; e.g. 1=> same as thiscontrol), the minimum inhibition at the high plateau relative to the “0%Inhibition Control” (Imin, e.g. 0=> same as the no drug control) and theHill slope (nH) are determined by a non-linear least squares fitting ofthe mP values as a function of dose of the compound using an in-housesoftware based on the procedures described by Mosser et al., JALA, 2003,8: 54-63, using the following equation:

${mP} = {\frac{\left( {{0\%\mspace{14mu}{mP}} - {100\%\mspace{14mu}{mP}}} \right)\left( {{I\;\max} - {I\;\min}} \right)}{1 + \left\lbrack \frac{\lbrack{Drug}\rbrack}{\left( {10^{- {pK}_{I}}\left( {1 + \frac{\lbrack{Substrate}\rbrack}{K_{M}}} \right)} \right.} \right\rbrack^{nH}} + {100\%\mspace{14mu}{mP}} + {\left( {{0\%\mspace{14mu}{mP}} - {100\%\mspace{14mu}{mP}}} \right)\left( {1 - {I\;\max}} \right)}}$

The median signal of the “0% inhibition controls” (0% mP) and the mediansignal of the “100% inhibition controls” (100% mP) are constantsdetermined from the controls located in columns 1-2 and 23-24 of eachassay plate. An apparent (K_(m)) for FAM-labeled cAMP of 150 nM wasdetermined in separate experiments through simultaneous variation ofsubstrate and selected drug concentrations.

Selectivity for PDE10, as compared to other PDE families, was assessedusing the IMAP® technology. Rhesus PDE2A3 and Human PDE10A2 enzyme wasprepared from cytosolic fractions of transiently transfected HEK cells.All other PDE's were GST Tag human enzyme expressed in insect cells andwere obtained from BPS Bioscience (San Diego, Calif.): PDE1A(Cat#60010), PDE3A (Cat#60030), PDE4A1A (Cat#60040), PDE5A1 (Cat#60050),PDE6C (Cat#60060), PDE7A (Cat#60070), PDE8A1 (Cat#60080), PDE9A2(Cat#60090), PDE11A4 (Cat#60110).

Assays for PDE 1 through 11 were performed in parallel at roomtemperature in 384-well microtiter plates with an incubation volume of20.2 μL. Solutions of test compounds were prepared in DMSO and seriallydiluted with DMSO to yield 30 μL of each of ten solutions differing by3-fold in concentration, at 32 serial dilutions per plate. 100%inhibition was determined by adding buffer in place of the enzyme and 0%inhibition is determined by using DMSO (1% final concentrations). ALabcyte POD 810 (Labcyte, Sunnyvale, Calif.) was used to dispense 200 nLfrom each well of the titration plate to make eleven copies of the assayplate for each titration, one copy for each PDE enzyme. A solution ofeach enzyme (dilution from aliquots, sufficient to produce 20% substrateconversion) and a separate solution of FAM-labeled cAMP or FAM-labeledcGMP from Molecular Devices (Sunnyvale, Calif., product # R7506 orcGMP#R7508), at a final concentration of 50 nM were made in the assaybuffer (10 mM Tris HCl, pH 7.2, 10 mM MgCl₂, 0.05% NaN₃ 0.01% Tween-20,and 1 mM DTT). Note that the substrate for PDE2 is 50 nM FAM cAMPcontaining 1000 nM of cGMP. The enzyme and the substrate were then addedto the assay plates in two consecutive additions of 10 μL, and thenshaken to mix. The reaction was allowed to proceed at room temperaturefor 60 minutes. A binding solution was then made from the kitcomponents, comprised of 80% Solution A, 20% Solution B and bindingreagent at a volume of 1/600 the total binding solution. The enzymaticreaction was stopped by addition of 60 μL, of the binding solution toeach well of the assay plate. The plates were sealed and shaken for 10seconds. The plates were incubated at room temperature for one hour,then the parallel and perpendicular fluorescence was measured using aTecan Genios Pro plate reader (Tecan, Switzerland). The apparentinhibition constants for the compounds against all 11 PDE's wasdetermined from the parallel and perpendicular fluorescent readings asdescribed for PDE10 FP assay using the following apparent K_(M) valuesfor each enzyme and substrate combination: PDE1A (FAM cGMP) 70 nM,rhesus PD2A3 (FAM cAMP) 10,000 nM, PDE3A (FAM cAMP) 50 nM, PDE4A1A (FAMcAMP) 1500 nM, PDE5A1 (FAM cGMP) 400 nM, PDE6C (FAM cGMP) 700 nM, PDE7A(FAM cAMP) 150 nM, PDE8A1 (FAM cAMP) 50 nM, PDE9A2 (FAM cGMP) 60 nM,PDE10A2 (FAM cAMP) 150 nM, PDE11A4 (FAM cAMP) 1000 nM. The intrinsicPDE10 inhibitory activity of a compound which may be used in accordancewith the present invention may be determined by these assays.

The compounds of the following examples had activity in inhibiting thehuman PDE10 enzyme in the aforementioned assays, generally with a Ki ofless than about 1 μM. Many of compounds within the present invention hadactivity in inhibiting the human PDE10 enzyme in the aforementionedassays, generally with a Ki of less than about 0.1 μM. Additional datais provided in the following Examples. Such a result is indicative ofthe intrinsic activity of the compounds in use as inhibitors of thePDE10 enzyme. In general, one of ordinary skill in the art wouldappreciate that a substance is considered to effectively inhibit PDE10activity if it has a Ki of less than or about 1 μM, preferably less thanor about 0.1 μM. The present invention also includes compounds withinthe generic scope of the invention which possess activity as inhibitorsof other phosphodiesterase enzymes.

The subject compounds may be further useful in a method for theprevention, treatment, control, amelioration, or reduction of risk ofthe diseases, disorders and conditions noted herein. The subjectcompounds may be further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of theaforementioned diseases, disorders and conditions in combination withother agents. The compounds of the present invention may be used incombination with one or more other drugs in the treatment, prevention,control, amelioration, or reduction of risk of diseases or conditionsfor which compounds of the present invention or the other drugs may haveutility, where the combination of the drugs together are safer or moreeffective than either drug alone. Such other drug(s) may beadministered, by a route and in an amount commonly used therefore,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of the present invention may be desirable. However, thecombination therapy may also include therapies in which the compound ofthe present invention and one or more other drugs are administered ondifferent overlapping schedules. It is also contemplated that when usedin combination with one or more other active ingredients, the compoundsof the present invention and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions of the present invention include those thatcontain one or more other active ingredients, in addition to a compoundof the present invention. The above combinations include combinations ofa compound of the present invention not only with one other activecompound, but also with two or more other active compounds. Likewise,compounds of the present invention may be used in combination with otherdrugs that are used in the prevention, treatment, control, amelioration,or reduction of risk of the diseases or conditions for which compoundsof the present invention are useful. Such other drugs may beadministered, by a route and in an amount commonly used therefore,contemporaneously or sequentially with a compound of the presentinvention. Accordingly, the pharmaceutical compositions of the presentinvention include those that also contain one or more other activeingredients, in addition to a compound of the present invention. Theweight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith another agent, the weight ratio of the compound of the presentinvention to the other agent will generally range from about 1000:1 toabout 1:1000, such as about 200:1 to about 1:200. Combinations of acompound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

Accordingly, the subject compounds may be used alone or in combinationwith other agents which are known to be beneficial in the subjectindications or other drugs that affect receptors or enzymes that eitherincrease the efficacy, safety, convenience, or reduce unwanted sideeffects or toxicity of the compounds of the present invention. Thesubject compound and the other agent may be co-administered, either inconcomitant therapy or in a fixed combination.

In one embodiment, the subject compound may be employed in combinationwith anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretaseinhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen,vitamin E, and anti-amyloid antibodies.

In another embodiment, the subject compound may be employed incombination with sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as: adinazolam, allobarbital, alonimid,alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine,aripiprazole, atypical antipsychotics, bentazepam, benzoctamine,brotizolam, bupropion, busprione, butabarbital, butalbital, capuride,carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam,cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine,clozapine, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam,ethchlorvynol, etomidate, fenobam, flunitrazepam, flupentixol,fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam,glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium,lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin,mephobarbital, meprobamate, methaqualone, midaflur, midazolam,nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam,paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine,phenelzine, phenobarbital, prazepam, promethazine, propofol,protriptyline, quazepam, quetiapine, reclazepam, risperidone,roletamide, secobarbital, sertraline, suproclone, temazepam,thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone,triazolam, trepipam, tricetamide, triclofos, trifluoperazine,trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon,ziprasidone, zolazepam, zolpidem, and salts thereof, and combinationsthereof, and the like, or the subject compound may be administered inconjunction with the use of physical methods such as with light therapyor electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole. It will be appreciated that thedopamine agonist may be in the form of a pharmaceutically acceptablesalt, for example, alentemol hydrobromide, bromocriptine mesylate,fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.Lisuride and pramipexol are commonly used in a non-salt form.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone. It will be appreciated that theneuroleptic agents when used in combination with the subject compoundmay be in the form of a pharmaceutically acceptable salt, for example,chlorpromazine hydrochloride, mesoridazine besylate, thioridazinehydrochloride, acetophenazine maleate, fluphenazine hydrochloride,flurphenazine enathate, fluphenazine decanoate, trifluoperazinehydrochloride, thiothixene hydrochloride, haloperidol decanoate,loxapine succinate and molindone hydrochloride. Perphenazine,chlorprothixene, clozapine, haloperidol, pimozide and risperidone arecommonly used in a non-salt form. Thus, the subject compound may beemployed in combination with acetophenazine, alentemol, aripiprazole,amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine,chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine,haloperidol, levodopa, levodopa with benserazide, levodopa withcarbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide,olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine,risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine,thiothixene, trifluoperazine or ziprasidone.

In another embodiment, the subject compound may be employed incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors (including tertiary amine tricyclicsand secondary amine tricyclics), selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors ofmonoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, 5-HT_(1A) agonists orantagonists, especially 5-HT_(1A) partial agonists, and corticotropinreleasing factor (CRF) antagonists. Specific agents include:amitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, maprotiline, nortriptyline and protriptyline;fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid,phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine;duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone andviloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate,diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone,flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptablesalts thereof.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans. The terms “administration of” and or“administering a” compound should be understood to mean providing acompound of the invention or a prodrug of a compound of the invention tothe individual in need of treatment.

The term “composition” as used herein is intended to encompass a productcomprising specified ingredients in predetermined amounts orproportions, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. Such term in relation to pharmaceutical composition,is intended to encompass a product comprising the active ingredient(s),and the inert ingredient(s) that make up the carrier, as well as anyproduct which results, directly or indirectly, from combination,complexation or aggregation of any two or more of the ingredients, orfrom dissociation of one or more of the ingredients, or from other typesof reactions or interactions of one or more of the ingredients. Ingeneral, pharmaceutical compositions are prepared by uniformly andintimately bringing the active ingredient into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation. In thepharmaceutical composition the active object compound is included in anamount sufficient to produce the desired effect upon the process orcondition of diseases. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by mixing acompound of the present invention and a pharmaceutically acceptablecarrier.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients that are suitable for themanufacture of tablets. The tablets may be uncoated or they may becoated by known techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. Compositions for oral use may also be presented as hardgelatin capsules wherein the active ingredients are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin, or olive oil. Aqueous suspensions, oily suspensions,dispersible powders or granules, oil-in-water emulsions, and sterileinjectable aqueous or oleagenous suspension may be prepared by standardmethods known in the art. By “pharmaceutically acceptable” it is meantthe carrier, diluent or excipient must be compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

The subject compounds may be further useful in a method for theprevention, treatment, control, amelioration, or reduction of risk ofthe diseases, disorders and conditions noted herein. The dosage ofactive ingredient in the compositions of this invention may be varied,however, it is necessary that the amount of the active ingredient besuch that a suitable dosage form is obtained. The active ingredient maybe administered to patients (animals and human) in need of suchtreatment in dosages that will provide optimal pharmaceutical efficacy.The selected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment. The dosewill vary from patient to patient depending upon the nature and severityof disease, the patient's weight, special diets then being followed by apatient, concurrent medication, and other factors which those skilled inthe art will recognize. Generally, dosage levels of between 0.001 to 10mg/kg. of body weight daily are administered to the patient, e.g.,humans and elderly humans. The dosage range will generally be about 0.5mg to 1.0 g. per patient per day which may be administered in single ormultiple doses. In one embodiment, the dosage range will be about 0.5 mgto 500 mg per patient per day; in another embodiment about 0.5 mg to 200mg per patient per day; and in yet another embodiment about 5 mg to 50mg per patient per day. Pharmaceutical compositions of the presentinvention may be provided in a solid dosage formulation such ascomprising about 0.5 mg to 500 mg active ingredient, or comprising about1 mg to 250 mg active ingredient. The pharmaceutical composition may beprovided in a solid dosage formulation comprising about 1 mg, 5 mg, 10mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient. For oraladministration, the compositions may be provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, such as 1,5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750,800, 900, and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, suchas once or twice per day.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsand the requisite intermediates are in some cases commerciallyavailable, or can be prepared according to literature procedures or asillustrated herein. The compounds of this invention may be prepared byemploying reactions as shown in the following schemes, in addition toother standard manipulations that are known in the literature orexemplified in the experimental procedures. Substituent numbering asshown in the schemes does not necessarily correlate to that used in theclaims and often, for clarity, a single substituent is shown attached tothe compound where multiple substituents are allowed under thedefinitions hereinabove. Reactions used to generate the compounds ofthis invention are prepared by employing reactions as shown in theschemes and examples herein, in addition to other standard manipulationssuch as ester hydrolysis, cleavage of protecting groups, etc., as may beknown in the literature or exemplified in the experimental procedures.Starting materials are made according to procedures known in the art oras illustrated herein. The following abbreviations are used herein: h:hour; Me: methyl; Et: ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; Bn:benzyl; Ac: acetyl; THF: tetrahydrofuran; Boc: tert-butyloxycarbonyl;DCM: dichloromethane; DMA-DMA: N,N-dimethylacetamide dimethyl acetal;DME: 1,2-dimethoxyethane; DIPEA: N,N-diisopropylethylamine; DPPA:diphenylphosphorylazide; EDC:N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide; EtOAc: ethyl acetate;HOBt: hydroxybenzotriazole hydrate; TEA: triethylamine; DMF:N,N-dimethylformamide; rt: room temperature; HPLC: high performanceliquid chromatography; NMR: nuclear magnetic resonance; TLC: thin-layerchromatography.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart. In some cases the order of carrying out the foregoing reactionschemes may be varied to facilitate the reaction or to avoid unwantedreaction products. The following examples are provided so that theinvention might be more fully understood. These examples areillustrative only and should not be construed as limiting the inventionin any way.

Intermediate 1

Step 1:

1-[(benzyloxy)carbonyl]azetidine-3-carboxylic acid (1-2)

1-1 (4.5 g, 18.05 mmol) was dissolved in MeOH (90 mL) and 2 M NaOH (27mL, 54.2 mmol) was added. After stirring at room temperature for 3 h,the solution was concentrated to ˜20 mL. 1 M HCl was added to theresulting solution until pH reached 4 and the solution was extractedwith EtOAc (2×). The combined organic layer was dried over Na₂SO₄,filtered, and concentrated to provide 1-2 as a white solid. MS:m/z=236.2 (M+H).

Step 2:

benzyl 3-(1-methyl-1H-benzimidazol-2-yl)azetidine-1-carboxylate (1-3)

1-2 (3.0 g, 12.75 mmol) was dissolved in THF (64 mL) andN-methylbenzene-1,2-diamine (2.02 g, 16.58 mmol), EDC (2.93 g, 15.30mmol), HOAt (2.08 g, 15.30 mmol), and Hunig's base (6.7 mL, 38.3 mmol)were added. After stirring for 18 h at room temperature, the reactionsolution was concentrated. The residue was then dissolved in acetic acid(30 mL), stirred at room temperature for 2 h, the solvent wasconcentrated under reduced pressure. The residue was partitioned betweenethyl acetate and 5% aqueous NaHCO₃. The organic layer was dried overNa₂SO₄, filtered, and concentrated. The crude residue was purified bysilica gel chromatography (EtOAc/Hexanes) to provide 1-3 as an off-whitesolid. MS: m/z=322.4 (M+H).

Step 3:

2-(azetidin-3-yl)-1-methyl-1H-benzimidazole (Intermediate 1)

A solution of 1-3 (3.32 g, 10.33 mmol) in MeOH (52 mL) was subjected to2 cycles of the evacuation/backfilling with nitrogen and then treatedwith 10% Pd/C (1.1 g). The evacuation/backfilling with nitrogenprocedure was repeated two times and then the nitrogen atmosphere wasexchanged for a hydrogen atmosphere by evacuation/backfilling with aballoon of hydrogen. After stirring for 3 h under hydrogen at roomtemperature, the reaction mixture was filtered through celite, andwashed with additional MeOH (20 mL). The filtrate was concentrated toyield Intermediate 1 as brown solid. MS: m/z=188.2 (M+H).

Intermediate 2

Step 1:

2-(1-(6-chloro-2-methylpyrimidin-4-yl)azetidin-3-yl)-1-methyl-1H-benzo[d]imidazole(2-2)

Intermediate 1 (8.2 g, 43.8 mmol), 2-1 (8.2 g, 50.4 mmol) and Cs₂CO₃(21.4 g, 65.7 mmol) were suspended in DMA (100 mL) and the mixture wasstirred at 50° C. for 3 h. The mixture was cooled to rt, diluted withEtOAc (200 mL), and washed sequentially with water, brine, and water(150 mL each). The combined aqueous phase was back extracted with EtOAc(2×100 mL). The combined organic layer was dried over MgSO₄, filtered,and concentrated to give a brownish solid. The solid was triturated witha diethyl ether/DCM mixture (95/5) and then filtered and dried undervacuum to give 2-2 as a light brown solid. MS: m/z=314.2 (M+H).

Step 2:

2-(1-(6-hydrazinyl-2-methylpyrimidin-4-yl)azetidin-3-yl)-1-methyl-1H-benzo[d]imidazole(Intermediate 2)

Compound 2-2 (900 mg, 2.87 mmol), hydrazine hydrate (431 mg, 8.6 mmol)and K₂CO₃ (1.2 g, 8.6 mmol) were suspended in 2-MeTHF (8 mL) in a vialthat was capped and heated at 85° C. for 16 h. After cooling to roomtemperature, the reaction was filtered and the collected solids werewashed with water and ether and dried over suction to give Intermediate2 as a white solid. MS: m/z=310.3 (M+H).

The following intermediates were prepared in a similar manner bysubstituting the appropriate starting material:

Intermediate Structure 3

4

5

Intermediate 6

Step 1:

4-chloro-2-methyl-6-vinylpyrimidine (6-2)

A reaction vessel containing 6-1 (26.3 g, 161 mmol), potassiumtrifluoro(vinyl)borate (20 g, 149 mmol), cesium carbonate (97 g, 299mmol) and butyldi-1-adamantylphosphine (2.89 g, 8.06 mmol) was evacuatedand backfilled with nitrogen (3×). Toluene (452 ml) and water (45 mL)were added and the reaction was purged with nitrogen for 20 min.Finally, palladium acetate (0.905 g, 4.03 mmol) was added, the mixturewas purged with nitrogen for 10 min, and then heated at 100° C. for 2 h.The mixture was cooled to room temperature, diluted with EtOAc (200 mL),washed with water (2×200 mL), dried, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography(0-100% EtOAc/hexanes) to give 6-2 as a white solid. MS: m/z=155.1(M+H).

Step 2:

ethyl 2-(6-chloro-2-methylpyrimidin-4-yl)cyclopropanecarboxylate (6-3)

To a solution of 6-2 (15.0 g, 97 mmol) in toluene (300 mL) heating at100° C. under a nitrogen atmosphere was added a solution of ethyldiazoacetate (30.2 mL, 291 mmol) in toluene (100 mL) over 1.5 h. Heatingwas continued for 2 h after which the reaction mixture was cooled toroom temperature and concentrated to dryness. The residue waspartitioned between saturated sodium bicarbonate solution (1 L) andethyl acetate (1 L). The organic layer was separated, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The cruderesidue was purified by silica gel chromatography (0-100% EtOAc/hexanes)to give 6-3 (trans isomer) as a colorless oil. MS: m/z=241.1 (M+H).

Step 3:

2-((1R,2R)-2-(6-chloro-2-methylpyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole(6-4)

To a solution of N1-methylbenzene-1,2-diamine (5.08 g, 41.5 mmol) intoluene (100 mL) was added a 2M solution of trimethylaluminum (22.85 ml,45.7 mmol) in toluene dropwise over 2 h with periodic cooling in an icebath to prevent an exotherm. After addition was complete, the resultingdark brown mixture was warmed to room temperature and stirred for 15min. The mixture was re-cooled in an ice bath and a solution of 6-3 (5g, 20.8 mmol) in toluene (20 mL) was added drop-wise over 2 h, afterwhich the reaction was warmed to room temperature. After stirring for 18h, the reaction was cooled in an ice bath and slowly quenched withwater. The mixture was filtered through a pad of celite washing withethyl acetate. The filtrate was repeatedly washed with saturated copper(II) sulfate solution until a yellow orange organic layer was obtainedand no N1-methylbenzene-1,2-diamine was observed by LCMS. The organiclayer was dried over magnesium sulfate, filtered and concentrated invacuo to give the crude product which was purified by silica gelchromatography (0-100% EtOAc/hexanes) to afford racemic 6-4. The racemiccompound was further purified by preparative chiral SFC on a ChiralCelOJ-H column (3 cm id×25 cm length) eluting with 70% carbon dioxide/30%methanol with 0.1% triethylamine modifier in isocratic mode at 80mL/min. The first eluting peak was identified as the desired R,Renantiomer (6-4) and was used in subsequent steps. ¹H NMR (400 MHz,CDCl₃) δ 7.71-7.66 (m, 1H), 7.31-7.23 (m, 3H), 7.19 (s, 1H), 3.83 (s,3H), 2.86-2.79 (m, 2H), 2.67 (s, 3H), 1.96 (m, 2H); MS: m/z=299.2 (M+H).

Step 4:

2-((1R,2R)-2-(6-hydrazinyl-2-methylpyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole(Intermediate 6)

A slurry of 6-4 (4 g, 13.39 mmol), hydrazine hydrate (1.261 ml, 40.2mmol) and potassium carbonate (5.55 g, 40.2 mmol) in 2-MeTHF (100 ml)was heated at 80° C. for 16 h. After cooling to room temperature, thereaction mixture was partitioned between water and ethyl acetate. Theorganic layer was separated, dried over sodium sulfate, filtered andconcentrated to afford Intermediate 6 as a tan solid. MS: m/z=295.4(M+H).

The following intermediates were prepared in a similar manner bysubstituting the appropriate starting materials:

Intermediate Structure 7

8

9

Intermediate 10

Step 1:

3,3-difluoro-2-hydroxypropanenitrile (10-2)

To a solution of 1-ethoxy-2,2-difluoroethanol (10-1) (2.0 g, 16 mmol) inwater (16 mL) was added potassium cyanide (1.0 g, 16 mmol) followed bypotassium dihydrogen phosphate (2.2 g, 16 mmol). The mixture was stirredat room temperature for 90 min then poured into saturated aqueous sodiumcarbonate (50 mL) and extracted with ethyl acetate (3×50 mL). Thecombined organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo to afford 10-2 as a yellow oil that was usedwithout further purification.

Step 2:

3,3-difluoro-2-hydroxypropanamide (10-3)

A solution of 10-2 (600 mg, 5.6 mmol) in conc HCl (6.90 mL, 84.0 mmol)was stirred at room temperature for 16 h. The mixture was concentratedin vacuo and azeotroped with toluene (2×) to provide 10-3 that was usedwithout further purification. ¹H NMR (400 MHz, d₆-DMSO) δ 7.48 (br s,1H), 7.36-7.10 (m, 2H), 6.34-5.97 (m, 1H), 4.34-4.09 (m, 1H).

Step 3:

2-((tert-butyldimethylsilyl)oxy)-3,3-difluoropropanamide (Intermediate10)

To a solution of 3,3-difluoro-2-hydroxypropanamide (700 mg, 5.6 mmol) inDMF (5.6 mL) was added tert-butyldimethylchlorosilane (1.10 g, 7.28mmol) and triethylamine (1.17 mL, 8.40 mmol). The mixture was stirred atroom temperature for 3 h, diluted with ethyl acetate and washed withsaturated aqueous sodium bicarbonate (2×) and brine. The organic layerwas dried over sodium sulfate, filtered, and concentrated to provideIntermediate 10 that was used without further purification. MS:m/z=240.3 (M+H).

Intermediate 11

Step 1:

benzyl 3-fluoro-2-hydroxypropanoate (11-2)

To a solution of 1-phenylethanaminium 3-fluoro-2-hydroxypropanoate(11-1) (0.14 g, 0.61 mmol) in DMF (1 mL) was added benzyl bromide (0.087mL, 0.73 mmol). The mixture was stirred at room temperature overnight,diluted with EtOAc, washed with water and brine, dried over sodiumsulfate, filtered, and concentrated. The residue was purified by silicagel chromatography (0-50% EtOAc/hexanes) to provide 11-2. HRMS: 198.0688found, 198.0692 required (M+).

Step 2:

3-fluoro-2-hydroxypropanamide (11-3)

A solution of 11-2 (0.20 g, 1.01 mmol) in 7M ammonia/MeOH (2.88 mL, 20.2mmol) was heated at 70° C. in a sealed vial overnight. The mixture wasconcentrated in vacuo to provide crude 11-3 that was used withoutfurther purification.

Step 3:

2-((tert-butyldimethylsilyl)oxy)-3-fluoropropanamide (Intermediate 11)

To a crude solution of 11-3 (0.050 g, 0.47 mmol) in DMF (0.5 mL) wasadded tert-butyldimethylchlorosilane (0.091 g, 0.61 mmol) andtriethylamine (0.098 mL, 0.70 mmol). The mixture was stirred at roomtemperature for 1 h then diluted with EtOAc. The mixture was washed withsaturated aqueous sodium bicarbonate (2×) and brine. The organic layerwas dried over sodium sulfate, filtered, and concentrated, providingcrude Intermediate 11 that was used without further purification. MS:m/z=222.3 (M+H).

Intermediate 12

Step 1:

4,4,4-trifluoro-2-hydroxybutanoic acid (12-2)

A solution of 2-amino-4,4,4-trifluorobutanoic acid (12-1) (1 g, 6.37mmol) in 1 N aqueous sulfuric acid (10.00 ml, 10 mmol) was cooled to 0°C. To the cooled reaction mixture was added a solution of sodium nitrite(1.1 g, 15.9 mmol) in water (5 mL) dropwise over 40 minutes via additionfunnel. The reaction mixture was then warmed to room temperature andstirred for 16 h. Sodium chloride was added to the reaction untilcomplete saturation was achieved. The resulting aqueous mixture waswashed with ethyl acetate (3×50 mL) and the combined organic layer wasdried over sodium sulfate, filtered and concentrated to dryness toafford 12-2 as a white crystalline solid. ¹H NMR (500 MHz, DMSO-d₆) δ2.51 (m, 1H), 2.67 (m, 1H), 4.24 (dd, J=8.60, 3.60 Hz, 1H), 5.74 (br s,1H), 12.89 (br s, 1H).

Step 2:

methyl 4,4,4-trifluoro-2-hydroxybutanoate (12-3)

Thionyl chloride (0.139 ml, 1.90 mmol) was added dropwise to a solutionof 12-2 (200 mg, 1.27 mmol) in MeOH (2 ml) at room temperature. Afteraddition was complete, the reaction was heated in a sealed vessel at 70°C. for 2 h. The reaction was cooled to room temperature and concentratedin vacuo. The residue was diluted with 7N NH₃/MeOH (3 mL) and filteredto remove insolubles. The filtrate was concentrated to dryness to afford12-3 as a clear oil.

Step 3:

4,4,4-trifluoro-2-hydroxybutanamide (Intermediate 12)

A solution of 12-3 (200 mg, 1.16 mmol) in 7N NH₃/MeOH (10 mL) was heatedat 70° C. overnight. The reaction mixture was filtered, and the filtratewas concentrated to dryness. The residue was dissolved in1,2-dimethoxyethane (10 mL) and filtered to remove insolubles. Thefiltrate was concentrated to dryness to afford Intermediate 12. ¹H NMR(500 MHz, DMSO-d₆) δ 7.40 (br s, 1H), 7.34 (br s, 1H), 5.93 (m, 1H),4.10 (m, 1H), 2.64-2.65 (m, 1H), 2.40-2.41 (m, 1H).

Intermediate 13

Step 1:

(S)-2-((tert-butyldimethylsilyl)oxy)propanamide (13-2)

A solution of (S)-2-hydroxypropanamide (13-1) (30 g, 337 mmol) andtert-butyldimethylchlorosilane (66.0 g, 438 mmol) in pyridine (101 ml,1246 mmol) and DMF (90 ml) was stirred at room temperature for 16 h. Thereaction mixture was filtered to remove insolubles and the filtrate waspartitioned between saturated aqueous sodium bicarbonate solution (500mL) and EtOAc (500 mL). The organic layer was washed with saturatedaqueous sodium bicarbonate solution (2×100 mL), brine (3×100 mL) andwater (3×100 mL). The organic layer was dried over sodium sulfate,filtered and concentrated to afford 13-2 as a viscous yellow oil. MS:m/z=204.0 (M+H).

Step 2:

(S)-2-((tert-butyldimethylsilyl)oxy)-N-(1-(dimethylamino)ethylidene)propanamide(Intermediate 13)

A solution of 13-2 (3.8 g, 18.69 mmol) and1,1-dimethoxy-N,N-dimethylethanamine (2 g, 15.02 mmol) in1,2-dimethoxyethane (40 ml) was heated at 80° C. under nitrogen in asealed tube for 2 h. The resulting reaction mixture containingIntermediate 13 was carried forward without purification or furthercharacterization. MS: m/z=273.4 (M+H).

The following intermediates were prepared in a similar manner toIntermediate 13. The required primary amide starting materials wereeither commercially available or prepared by routes described forIntermediates 10-12.

Intermediate Structure 14

15

16

17

18

19

20

21

22

23

24

Example 1

(S)-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol(Example 1)

A solution of Intermediate 2 (11.0 g, 35.6 mmol) in AcOH (100 mL) wasadded to crude Intermediate 13 (24.2 g, 89 mmol, prepared by heating thecorresponding primary amide in neat DMA-DMA at 50° C. overnight followedby removal of excess DMA-DMA by rotary evaporation). The reactionmixture was allowed to stir for 10 min at room temperature and thenheated at 80° C. for 1 h. Sampling of the reaction by LCMS suggestedcyclization to the silyl-protected hydroxy triazole had occurred. Thereaction was allowed to stir at 80° C. for an additional 16 h at whichpoint complete de-silylation of the hydroxy group had occurred. Thereaction was cooled to room temperature, poured carefully over saturatedaqueous sodium bicarbonate solution (200 mL), and the aqueous layer wasmade basic to pH˜8 by the addition of solid sodium bicarbonate. Thesolution was extracted with ethyl acetate and the organic layer wasdried over sodium sulfate, filtered, and concentrated. The crude productwas purified by silica gel chromatography (0-10% 2-propanol/DCM) to giveExample 1 as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.76-7.74 (m, 1H),7.35-7.28 (m, 3H), 6.96 (m, 1H), 6.62 (s, 1H), 5.12-5.07 (m, 1H),4.71-4.58 (br s, 4H), 4.34-4.24 (m, 1H), 3.75 (s, 3H), 2.54 (s, 3H),2.43 (s, 3H) 1.71 (d, J=6.6 Hz, 3H); MS: m/z=405.5 (M+H).

Example 2

(R)-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol(Example 2)

To a solution of Intermediate 2 (1.2 g, 3.9 mmol) in AcOH (35 mL) wasadded the DME solution of Intermediate 14 (5.1 g, 18.7 mmol). Thereaction mixture was allowed to stir for 10 min at room temperature andthen heated at 80° C. for 30 min. Sampling of the reaction by LCMSsuggested cyclization to the silyl-protected hydroxy triazole hadoccurred. The DME was removed by rotary evaporation and the remainingmixture was allowed to stir at 80° C. for an additional 16 h at whichpoint complete de-silylation of the hydroxy group had occurred. Thereaction was cooled to room temperature, poured carefully over saturatedaqueous sodium bicarbonate solution (200 mL), and the aqueous layer wasmade basic to pH˜8 by the addition of solid sodium bicarbonate. Thesolution was extracted with ethyl acetate (200 mL) and the organic layerwas dried over sodium sulfate, filtered, and concentrated. The crudeproduct was purified by silica gel chromatography (0-10% 2-propanol/DCM)to give Example 2 as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.77-7.75(m, 1H), 7.35-7.24 (m, 3H), 6.95 (m, 1H), 6.62 (s, 1H), 5.12-5.07 (m,1H), 4.68-4.58 (br s, 4H), 4.34-4.28 (m, 1H), 3.75 (s, 3H), 2.54 (s,3H), 2.43 (s, 3H) 1.71 (d, J=6.6 Hz, 3H); MS: m/z=405.3 (M+H).

Example 3

2,2,2-trifluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol(Example 3)

To a solution of Intermediate 2 (5.5 g, 17.8 mmol) in AcOH (60 mL) wasadded the DME solution of Intermediate 18 (7.5 g, 35.6 mmol) and thereaction was heated at 80° C. for 1 h. Sampling of the reaction by LCMSsuggested cyclization to the triazole had occurred with concomitantdesilylation of the hydroxy group. The reaction was cooled to roomtemperature and brought to pH˜8 by the slow addition of saturatedaqueous sodium bicarbonate. The aqueous phase was extracted with EtOAcand the organic layer was dried over sodium sulfate, filtered, andconcentrated. The crude product was purified by silica gelchromatography (0-10% 2-propanol/DCM) to give racemic Example 3. MS:m/z=459.3 (M+H).

The racemic mixture was separated by preparative chiral SFC on aChiraltech ID column (2 cm id×25 cm length) eluting with 65% carbondioxide/35% 2-propanol with 0.1% diethylamine modifier in isocratic modeat 50 mL/min.

Example 3a (1^(st) eluting): ¹H NMR (500 MHz, CDCl₃) δ 9.34-9.26 (m,1H), 7.77-7.75 (m, 1H), 7.34-7.28 (m, 3H), 6.63 (s, 1H), 5.54-5.50 (m,1H), 4.75-4.58 (br s, 4H), 4.33-4.30 (m, 1H), 3.75 (s, 3H), 2.53 (s,3H), 2.46 (s, 3H); MS: m/z=459.5 (M+H).

Example 3b (2nd eluting): ¹H NMR (500 MHz, CDCl₃) δ 9.33-9.31 (m, 1H),7.77-7.75 (m, 1H), 7.35-7.28 (m, 3H), 6.63 (s, 1H), 5.56-5.51 (m, 1H),4.76-4.56 (br s, 4H), 4.33-4.30 (m, 1H), 3.75 (s, 3H), 2.53 (s, 3H),2.46 (s, 3H); MS: m/z=459.5 (M+H).

The following Examples were prepared in a similar manner by substitutingthe appropriate starting materials. Racemic compounds were separated bychiral SFC in a manner similar to Example 3 to provide enantiomers thatare designated as ‘first eluting’ or ‘second eluting’.

MS m/z Example Structure Name (M + H)  4 

1-(3-methyl-1-(2-methyl-6-(3-(1- methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H- 1,2,4-triazol-5-yl)propan-1-ol419.5  4a

1-(3-methyl-1-(2-methyl-6-(3-(1- methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H- 1,2,4-triazol-5-yl)propan-1-ol -1^(st) eluting 419.3  4b

1-(3-methyl-1-(2-methyl-6-(3-(1- methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H- 1,2,4-triazol-5-yl)propan-1-ol -2^(nd) eluting 419.3  5 

2-methyl-1-(3-methyl-1-(2-methyl-6- (3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H- 1,2,4-triazol-5-yl)propan-1-ol433.5  5a

2-methyl-1-(3-methyl-1-(2-methyl-6- (3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H- 1,2,4-triazol-5-yl)propan-1-ol -1^(st) eluting 433.5  5b

2-methyl-1-(3-methyl-1-(2-methyl-6- (3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H- 1,2,4-triazol-5-yl)propan-1-ol -2^(nd) eluting 433.5  6 

cyclopropyl(3-methyl-1-(2-methyl-6- (3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H- 1,2,4-triazol-5-yl)methanol 431.5 6a

cyclopropyl(3-methyl-1-(2-methyl-6- (3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H- 1,2,4-triazol-5-yl)methanol -1^(st) eluting 431.5  6b

cyclopropyl(3-methyl-1-(2-methyl-6- (3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H- 1,2,4-triazol-5-yl)methanol -2^(nd) eluting 431.5  7 

3,3,3-trifluoro-1-(3-methyl-1-(2- methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1- yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol 473.3  7a

3,3,3-trifluoro-1-(3-methyl-1-(2- methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1- yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol - 1^(st) eluting 473.3  7b

3,3,3-trifluoro-1-(3-methyl-1-(2- methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1- yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol - 2^(nd) eluting 473.3  8 

1-(3-methyl-1-(6-(3-(1-methyl-1H- benzo[d]imidazol-2-yl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)- 1H-1,2,4-triazol-5-yl)ethanol 459.5 8a

1-(3-methyl-1-(6-(3-(1-methyl-1H- benzo[d]imidazol-2-yl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)- 1H-1,2,4-triazol-5-yl)ethanol -1^(st) eluting 459.4  8b

1-(3-methyl-1-(6-(3-(1-methyl-1H- benzo[d]imidazol-2-yl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)- 1H-1,2,4-triazol-5-yl)ethanol -2^(nd) eluting 459.5  9 

1-(1-(2-methoxy-6-(3-(1-methyl-1H- benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-3-methyl-1H- 1,2,4-triazol-5-yl)ethanol 421.5 10 

1-(1-(2-cyclopropyl-6-(3-(1-methyl- 1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-3-methyl-1H- 1,2,4-triazol-5-yl)ethanol 431.5 10a

1-(1-(2-cyclopropyl-6-(3-(1-methyl- 1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-3-methyl-1H- 1,2,4-triazol-5-yl)ethanol - 1^(st)eluting 431.5 10b

1-(1-(2-cyclopropyl-6-(3-(1-methyl- 1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-3-methyl-1H- 1,2,4-triazol-5-yl)ethanol - 2^(nd)eluting 431.5 11a

2,2-difluoro-1-(3-methyl-1-(2- methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1- yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol - 1^(st) eluting 441.3 11b

2,2-difluoro-1-(3-methyl-1-(2- methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1- yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol - 2^(nd) eluting 441.4 12 

2-fluoro-1-(3-methyl-1-(2-methyl-6- (3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H- 1,2,4-triazol-5-yl)ethanol 423.3

Example 13

Step 1:

2-((1R,2R)-2-(6-(5-((S)-1-((tert-butyldimethylsilyl)oxy)ethyl)-3-methyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole(13-1)

To a solution of Intermediate 6 (1.8 g, 6.1 mmol) in acetic acid (40 ml)was added Intermediate 13 (4.0 g, 14.7 mmol) as a crude reaction mixturein 1,2-dimethoxyethane (40 mL). The reaction mixture was allowed to stirfor 5 minutes at room temperature and then heated at 80° C. for 1 h. Thereaction was cooled to room temperature, poured carefully over saturatedaqueous sodium bicarbonate solution (200 mL), and the aqueous layer wasmade basic to pH˜8 by the addition of solid sodium bicarbonate. Thesolution was extracted with ethyl acetate (200 mL) and the organic layerwas dried over sodium sulfate, filtered and concentrated. The crudeproduct was purified by silica gel chromatography (0-60% EtOAc/hexanes)to afford 13-1 as an oil. MS: m/z=504.4 (M+H).

Step 2:

(S)-1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol(Example 13)

A solution of 13-1 (2.8 g, 5.6 mmol), acetic acid (0.41 ml, 7.2 mmol)and 1 N tetrabutylammonium fluoride (7.8 mL, 7.8 mmol) in THF (15.6 ml)was stirred at 23° C. for 16 h. Additional 1 N tetrabutylammoniumfluoride in THF (4 mL, 4 mmol) was added and stirring was continued for16 h. The white precipitate that formed was collected by filtration,washed with THF (2×50 mL) followed by ether (2×50 mL). The white solidwas dissolved in DCM (100 mL) and washed with saturated aqueous sodiumbicarbonate solution (2×100 mL), brine (2×100 mL) and water (2×100 mL)successively. The organic layer was dried over sodium sulfate, filtered,and concentrated to afford a clear oil. The oil was triturated from 5:1ether/EtOAc and the resulting white solid was collected by filtrationand air dried to provide Example 13. ¹H NMR (500 MHz, CDCl₃) δ 7.77 (s,1H), 7.71-7.69 (m, 1H), 7.32-7.24 (m, 3H), 6.12 (d, 1H, J=5.4 Hz),5.19-5.17 (m, 1H), 3.83 (s, 3H), 2.89-2.86 (m, 2H), 2.73 (s, 3H), 2.44(s, 3H), 2.09-2.00 (m, 2H), 1.73 (d, 3H, J=6.6 Hz); MS: m/z=390.3 (M+H).

The following Examples were prepared in a similar manner by substitutingthe appropriate starting materials:

MS m/z Example Structure Name (M + H) 14

(R)-1-(3-methyl-1-(2-methyl-6- ((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2- yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol 390.3 15

(R)-(3-methyl-1-(2-methyl-6- ((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2- yl)cyclopropyl)pyrimidin-4-yl)- 1H-1,2,4-triazol-5-yl)(phenyl)methanol 452.5 16

(S)-(3-methyl-1-(2-methyl-6- ((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2- yl)cyclopropyl)pyrimidin-4-yl)- 1H-1,2,4-triazol-5-yl)(phenyl)methanol 452.5 17

(S)-1-(3-methyl-1-(6-((1R,2R)-2- (1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)-2- (trifluoromethyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol 444.2 18

(S)-1-(1-(2-cyclopropyl-6- ((1R,2R)-2-(1-methyl-1H- benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-3- methyl-1H-1,2,4-triazol-5- yl)ethanol416.3

Example 19

1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol(Example 19)

To a mixture of Intermediate 6 (50 mg, 0.17 mmol) in AcOH (3 mL) wasadded the DME solution of Intermediate 22 (116 mg, 0.55 mmol) in oneportion. The reaction was heated at 80° C. for 30 min and then cooled toroom temperature. The mixture was partitioned between saturated aqueoussodium bicarbonate and EtOAc and the aqueous layer was adjust to pH˜8.The organic layer was dried over sodium sulfate, filtered, andconcentrated. The crude product was purified by reverse-phase HPLC(5-95% ACN/water containing 0.1% NH₄OH, Phenomenex Axia) to affordExample 19 as a mixture of diastereomers at the secondary alcoholcarbon. ¹H NMR (500 MHz, CDCl₃) δ 7.76 (s, 1H), 7.71-7.69 (m, 1H),7.31-7.25 (m, 3H), 5.96-5.89 (m, 1H), 4.99-4.95 (m, 1H), 3.84 (s, 3H),2.89-2.86 (m, 2H) 2.73 (s, 3H), 2.43 (s, 3H), 2.11-1.99 (m, 4H),1.10-1.03 (m, 3H); MS: m/z=404.5 (M+H).

The mixture of diastereomers was separated by preparative chiral SFC ona ChiralPak AD-H column (3 cm id×25 cm length) eluting with 80% carbondioxide/20% MeOH with 0.1% diethylamine modifier in isocratic mode at 80mL/min.

Example 19a (1^(st) eluting): ¹H NMR (500 MHz, CDCl₃) δ 7.76 (s, 1H),7.71-7.69 (m, 1H), 7.31-7.25 (m, 3H), 5.95 (d, J=7.0 Hz, 1H), 4.99-4.95(m, 1H), 3.84 (s, 3H), 2.89-2.86 (m, 2H) 2.73 (s, 3H), 2.43 (s, 3H),2.11-1.99 (m, 4H), 1.10-1.03 (m, 3H); MS: m/z=404.5 (M+H).

Example 19b (2nd eluting): ¹H NMR (500 MHz, CDCl₃) δ 7.76 (s, 1H),7.71-7.69 (m, 1H), 7.31-7.25 (m, 3H), 5.89 (d, J=6.6 Hz, 1H), 4.99-4.95(m, 1H), 3.83 (s, 3H), 2.89-2.86 (m, 2H) 2.73 (s, 3H), 2.43 (s, 3H),2.11-1.99 (m, 4H), 1.10-1.03 (m, 3H); MS: m/z=404.5 (M+H).

The following Examples were prepared in a similar manner by substitutingthe appropriate starting materials. When applicable, diastereomericcompound mixtures were separated by chiral SFC in a manner similar toExample 19 to provide diastereomers that are designated as ‘firsteluting’ or ‘second eluting’.

MS m/z Example Structure Name (M + H) 20 

2,2,2-trifluoro-1-(3-methyl- 1-(2-methyl-6-((1R,2R)-2- (1-methyl-1H-benzo[d]imidazol-2- yl)cyclopropyl)pyrimidin-4- yl)-1H-1,2,4-triazol-5-yl)ethanol 444.4 20a

2,2,2-trifluoro-1-(3-methyl- 1-(2-methyl-6-((1R,2R)-2- (1-methyl-1H-benzo[d]imidazol-2- yl)cyclopropyl)pyrimidin-4- yl)-1H-1,2,4-triazol-5-yl)ethanol - 1^(st) eluting 444.4 20b

2,2,2-trifluoro-1-(3-methyl- 1-(2-methyl-6-((1R,2R)-2- (1-methyl-1H-benzo[d]imidazol-2- yl)cyclopropyl)pyrimidin-4- yl)-1H-1,2,4-triazol-5-yl)ethanol - 2^(nd) eluting 444.4 21 

2-methyl-1-(3-methyl-1-(2- methyl-6-((1R,2R)-2-(1- methyl-1H-benzo[d]imidazol-2- yl)cyclopropyl)pyrimidin-4- yl)-1H-1,2,4-triazol-5-yl)propan-1-ol 418.5

The following table shows representative data for the compounds of theExamples as PDE10 inhibitors as determined by the foregoing assays. Inthis table, the PDE10 Ki is a measure of the ability of the testcompound to inhibit the action of the PDE10 enzyme.

Example PDE10a Ki (nM)  1 0.23  2 1.2  3 0.11  3a 1.0  3b 0.06  4 0.51 4a 1.8  4b 0.41  5 0.41  5a 0.34  5b 0.77  6 0.36  6a 0.17  6b 2.6  73.2  7a 4.5  7b 2.5  8 0.83  8a 0.53  8b 1.0  9 1.2 10 0.21 10a 0.13 10b0.39 11a 0.65 11b 3.0 12 0.34 13 0.74 14 1.1 15 0.09 16 0.62 17 2.8 180.36 19 1.3 19a 0.55 19b 0.59 20 0.55 20a 0.58 20b 0.92 21 0.47

With respect to other substituted triazolyl compounds such as thosedisclosed in U.S. Ser. No. 61/544,055, the present compounds exhibitunexpected properties, such as improved potency against the PDE10 enzymeand reduced potential for drug-drug interactions based on CYPinhibition. This includes reversible inhibition of CYP2C9 andtime-dependent inhibition (TDI) of CYP3A4.

For example, the following compounds are disclosed in U.S. Ser. No.61/544,055:

2-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-2-ol(Compound A)

2-((1R,2R)-2-(6-(5-((S)-1-methoxyethyl)-3-methyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole(Compound B)

2-((1R,2R)-2-(6-(5-(methoxymethyl)-3-methyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole(Compound C)

Representative compounds herein are listed in the following Table andtheir properties with respect to PDE10 potency, CYP3A4 TDI, and CYP2C9inhibition are compared to those of Compounds A, B, and C.

Compound/ PDE10 Ki TDI CYP3A4 CYP2C9 Example (nM) shift ratio IC₅₀ (uM)A 4.2 1 >50 B 2.1 1 10.5 C 0.49 >1.98 46  1 0.23 1 >50  2 1.2 1 >50  3b0.06 1 >50  4b 0.51 1 >50  6a 0.17 1 >50 13 0.74 1 >50 14 1.1 1 >50 19a0.55 1 >50

As noted by this data, the compounds of the present invention asillustrated by Examples 1, 2, 3b, 4b, 6a, 13, 14, and 19a displayincreased potency against the PDE10 enzyme compared to Compounds A andB. This may translate into improved in vivo efficacy and the potentialfor a lower dose.

Further, Compound B inhibits the CYP2C9 enzyme with an IC₅₀ of 10.5 uMwhile Examples 1, 2, 3b, 4b, 6a, 13, 14, and 19a all have IC₅₀ valuesof >50 uM for inhibition of CYP2C9 and suggests that compounds of thepresent invention may have reduced risk for a CYP2C9 mediated drug-druginteraction as compared to Compound B.

Compound C has comparable potency against the PDE10 enzyme (Ki=0.49 nM)to many compounds of the present invention. However, this compoundexhibited time-dependent inhibition (TDI) of the CYP3A4 enzyme which isa development risk due to the potential for a drug-drug interaction inhumans (for a leading reference, see: Obach R S, Walsky R L, andVenkatakrishnan K (2007) Mechanism-based inactivation of humancytochrome P450 enzymes and the prediction of drug-drug interactions.Drug Metab Dispos 35:246-255). Examples 1, 2, 3b, 4b, 6a, 13, 14, and19a do not exhibit TDI of CYP3A4, suggesting a benefit for compounds ofthis type.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

What is claimed is:
 1. A compound of the formula I:

wherein: A represents

R represents H or C₁₋₆alkyl; R¹ is selected from the groups consistingof (CH₂)_(n)C₁₋₄haloalkyl, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₆₋₁₀aryl, saidalkyl cycloalkyl, and aryl is unsubstituted or substituted with 1 to 3groups of R^(a); R² is selected from the group consisting of H, O—R, CN,O(CH₂)_(n)OR, OCHR(CH₂)_(n)OR, SR, SO₂R, S(O)R, N(R)₂, C(O)N(R)₂, C₁₋₃haloalkyl, O(CH₂)_(n)C₁₋₃haloalkyl, O(CH₂)_(n)C₃₋₆cycloalkyl,(CH₂)_(n)C₅₋₁₀ heterocycle, C₁₋₆ alkyl, and C₃₋₁₀cycloalkyl, said alkyl,cycloalkyl, and heterocycle is unsubstituted or substituted with 1 to 3groups of R^(a); R^(a) is selected from the group consisting of: (1)halogen, (2) hydroxyl, (3) C₁₋₆alkyl, (4) —(CH₂)_(n)O—R, (5) (CH₂)_(n)C₆₋₁₀aryl, (6) (CH₂)_(n)C₅₋₁₀ heterocycle, (7) OC₁₋₅ haloalkyl; (8)CO₂R; (9) C(O)N(R)₂; (10) (CH₂)_(n)C(O)R; (11) CN, (12) (CH₂)_(n)N(R)₂;(13) (CH₂)_(n)C₃₋₆cycloalkyl, (14) (CH₂)_(n)C₁₋₃ haloalkyl; n represents0-4, or a pharmaceutically acceptable salt thereof.
 2. The compoundaccording to claim 1 wherein A is


3. The compound according to claim 1 wherein A is


4. The compound according to claim 1 wherein R¹ is C₁₋₆ alkyl.
 5. Thecompound according to claim 1 wherein R¹ is (CH₂)_(n)C₁₋₄ haloalkyl. 6.The compound according to claim 1 wherein R¹ is optionally substitutedC₆₋₁₀ aryl.
 7. The compound according to claim 1 wherein R¹ is C₃₋₆cycloalkyl.
 8. The compound according to claim 1 represented bystructural formula Ia:

or a pharmaceutically acceptable salt thereof, wherein R¹ is C1-6 alkyl,CF₃, C6-10 aryl, or C3-6 cycloalkyl.
 9. The compound according to claim8 wherein R¹ is methyl, ethyl, propyl, CF₃, phenyl, or cyclohexyl and R²is methyl, ethyl, propyl, CF₃, or cyclopropyl.
 10. The compoundaccording to claim 1 represented by structural formula Iaa:

or a pharmaceutically acceptable salt thereof, wherein R¹ is C1-6 alkyl,CF₃, C6-10 aryl, or C3-6 cycloalkyl.
 11. The compound according to claim10 wherein R¹ is methyl, ethyl, propyl, CF₃, phenyl, or cyclohexyl andR² is methyl, ethyl, propyl, CF₃, or cyclopropyl.
 12. The compoundaccording to claim 1 represented by structural formula Ib:

or a pharmaceutically acceptable salt thereof wherein R¹ is C1-6 alkyl,CF₃, C6-10 aryl, or C3-6 cycloalkyl.
 13. The compound according to claim12 wherein R¹ is methyl, ethyl, propyl, CF₃, phenyl, or cyclohexyl andR² is methyl, ethyl, propyl, CF₃, or cyclopropyl.
 14. A compound whichis:1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;(S)-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;(R)-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;1-(3-methyl-1-(6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;1-(1-(2-methoxy-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-3-methyl-1H-1,2,4-triazol-5-yl)ethanol;1-(1-(2-cyclopropyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-3-methyl-1H-1,2,4-triazol-5-yl)ethanol;2,2,2-trifluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;(S)-2,2,2-trifluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;(R)-2,2,2-trifluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;2,2-difluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;2-fluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;(S)-cyclohexyl(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)methanol;(R)-cyclohexyl(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)methanol;(S)-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)(phenyl)methanol;(R)-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)(phenyl)methanol;1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol;2-methyl-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol;cyclopropyl(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)methanol;3,3,3-trifluoro-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol;1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;(R)-1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;(S)-1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;(R)-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)(phenyl)methanol;(S)-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)(phenyl)methanol;2,2,2-trifluoro-1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol;2-methyl-1-(3-methyl-1-(2-methyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)propan-1-ol;1-(3-methyl-1-(6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)-2-(trifluoromethyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;(S)-1-(3-methyl-1-(6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)-2-(trifluoromethyl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol;1-(1-(2-cyclopropyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-3-methyl-1H-1,2,4-triazol-5-yl)ethanol(S)-1-(1-(2-cyclopropyl-6-((1R,2R)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)cyclopropyl)pyrimidin-4-yl)-3-methyl-1H-1,2,4-triazol-5-yl)ethanol;or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition which comprises a pharmaceutically acceptable carrier and acompound of claim 1 or a pharmaceutically acceptable salt thereof.
 16. Amethod for treating anxiety in a mammalian patient in need thereof whichcomprises administering to the patient a therapeutically effectiveamount of a compound of claim 1 or a pharmaceutically acceptable saltthereof.